1. Field of the Invention
This invention is directed generally to micelle compositions, methods of making micelles, and the use of micelle compositions with drugs for treatment of disease.
2. Description of the Prior Art
Cancer is a very deadly disease. Various cytoxic chemotherapy agents have been used to eradicate cancer and/or prevent the spread of the cancer. Alkylating agents, such as cisplatin and chlorambucil, crosslink NDA to prevent cell division. Antitumor antibiotics, such as dactinomycin and bleomycin, bind DNA and thus prevent DNA separation and mRNA synthesis. Antimetabolites, such as purine and pyrimidine antagonists and 5-fluorouracil, may mimic cell nutrients and prevent normal DNA synthesis. Plant alkaloids, such as paclitaxel and vinblastine, block cell division by blocking microtubule formation. Topoisomerase inhibitors, such as camptothecins, topotecan, and irinotecan, inhibit DNA supercoiling and block transcription and replication. Many drugs that are potentially efficacious for treating diseases such as cancer have poor solubility that limits their usefulness.
Rapamycin is a large, highly hydrophobic compound with applications in chemotherapy, immunosuppression, anti-restenosis, fungal infections, and neurological disorders. Rapamycin as an anti-cancer agent is generally formed as ester analogs which are quickly hydrolyzed and sequestered into the red blood cells thereby reducing the effectiveness of rapamycin at tumor sites. Rapamycin is currently used as an immunosuppressant for kidney transplant patients, Rapamune (Wyeth-Ayerst), and has shown long term clinical safety. However, rapamycin is a poorly water soluble drug, creating difficulties in drug administration in patients.
Geldanamycin is also a hydrophobic compound with applications including the treatment of cancer. Geldanamycin is a member of the new class of compounds known as heat shock protein inhibitors, having both anti-tumor and neurological disease applications. The mode of action is by inhibiting heat shock protein 90 (Hsp90), strongly binding to Hsp90 (Kd=1.2 μM), and preventing interaction with downstream components. Hsp 90 is a molecular chaperon responsible for the folding, stability, and function of numerous client proteins. Inhibition of Hsp 90 leads to the destabilization and eventual ubiquitination of many oncogenic client proteins. By targeting multiple oncogenic proteins, geldanamycin may be efficacious against a broad range of tumors and may increase the chances of overcoming drug resistance. In addition, the inhibition of Hsp90 leads to an up-regulation of Hsp70, which reduces the formation of abnormal tau species, the primary component of plaque deposits in Alzheimer's and Parkinson's disease.
Paclitaxel is another hydrophobic compound with applications including the treatment of cancer. Paclitaxel belongs to a group of medicines called antineoplastics, which inhibit cellular growth. The inhibition is accomplished by disrupting microtubule function by binding to the beta subunit of tubulin. The disrupted microtubule looses the ability to disassemble, a necessary function, for example, in chromosomal migration during cell replication. Additionally, research has indicated that paclitaxel induces apoptosis, programmed cell death, by binding to an apoptosis stopping protein called Bcl-2 and stopping its function.
Various techniques for solubilizing poorly soluble compounds exist, such as the formation of emulsions, liposomes, or micelles, all of which may have multiple phases, some of which may be unstable and may tend to separate.
Micelle systems based on amphiphilic polymers using block copolymers (ABC's) have been used to formulate such challenging drugs. ABC's comprised of a hydrophobic, such as polypropylene glycol), and hydrophilic block, such as polyethylene glycol (PEG), can assemble into a microphase separated, core/shell architecture in a selective solvent. PEG-poly(ε-caprolactone) (PEG-PCL) and PEG-poly(amino acids) can form these polymeric micelles. Alternatively, phospholipids can be used, such as, PEG-distearoylphosphatidylethanolamine (PEG-DSPE) to form these polymeric micelles. In an aqueous environment, the hydrophobic drug can be encapsulated into the hydrophobic core of the micelle and have aqueous solubility provided by a poly(ethylene glycol) (PEG) and corona (shell). Due to their nanoscopic dimensions and stealth properties imparted by a PEG corona, micelles may have long-term circulation capabilities. During the circulation period, the micelle may gradually release drug and eventually dissociate and be eliminated from circulation.
Excipients and co-excipients have been used to solubilize poorly soluble compounds. Alpha-tocopherol, commonly known as Vitamin E or simply tocopherol, has been used as an excipient because of its ring and alkyl chain structures common to many poorly-soluble drugs. Vitamin E is not toxic to living organisms. Additionally, tocopherol stabilizes biological membranes. Tocopherol, however, is not soluble in water and therefore it has had limited usefulness in intravenous solutions.